Familial adenomatous polyposis (FAP) is an autosomal dominant disorder which is linked to human chromosome 5q21 (Kinzler, K. W. et al. (1991) Science 253:661-665) in a region generally known as the adenomatous polyposis coli (APC) locus. FAP is characterized by the appearance of thousands of colorectal tumors (adenomatous polyps) which progress to colon carcinomas. Polyps also develop in the upper gastrointestinal tract and malignancies may occur in other sites including the brain and the thyroid. The APC locus is linked to other oncological diseases which involve gastrointestinal tissues, including hereditary flat adenoma syndrome (HFAS), Lynch syndrome, Gardner's syndrome, and Turcot's syndrome (Prieschl, E. E. et al. (1996) Gene 169:215-218).
Kinzler et al. (supra) isolated 6 contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA from the region linked to FAP on 5q21. Subclones from these contigs were used to identify and position six genes, all of which express in normal colonic mucosa. Two of these genes, the APC (adenomatous polyposis coli) gene and the MCC (mutated in colorectal cancers) gene were identified by their mutations in human colorectal tumors.
Joslyn, G. et al. (1991; Cell 66:601-613) and Groden, J. et al. (1991; Cell 66:589-600) characterized deletions of 100-260 kb in chromosome 5 from two unrelated patients with severe cases of FAP. MCC was shown to be located outside this deleted region. Three genes were identified within the deleted region: the APC gene; SRP19, which encodes the 19 kd component of the ribosomal signal recognition particle; and a novel gene designated DPl (deleted in polyposis 1), which is transcribed in the same orientation as MCC. AN RFLP marker correlating 100% with FAP maps to the 3' end of the DPl (Spirio, L. et al. (1991) Nucl. Acids Res. 19:6348, erratum Nucl. Acids Res. 20:642). DPl is nearly identical to TB2 (Kinzler et al. supra.
A homolog of DPl was recently identified in a mouse mast cell line (Prieschl et al., supra). Expression of the mouse homolog, designated GP160, is downregulated in the mast cell line approximately 2 hours following allergic (IgE plus antigen) stimulation but reappears 4-6 hours post-stimulation. A similar pattern of expression is observed for genes involved in growth arrest and for some molecules involved in T-cell signal transduction cascades. The expression pattern together with the presence of a kinase motif led Prieschl et al. to propose that GP106 may function in a signaling pathway.
The discovery of a new DPl homolog and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of neoplastic disorders.